Guthier C V, D'Amico A V, King M T, Nguyen P L, Orio P F, Sridhar S, Makrigiorgos G M, Cormack R A
Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Nanomedicine Science and Technology Center, Northeastern University, Boston, MA, USA.
Med Phys. 2018 Jun 15. doi: 10.1002/mp.13051.
In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio.
The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for I permanent prostate implants. Compound concentrations were calculated using steady-state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (ϕ ). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (c ). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion-elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other.
The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm , ϕ from 0.01 to 4 mm , c from 0.05 to 7.5 times the steady-state compound concentration released from the surface of the eluter. The number of used eluters (n ) was simulated from 10 to 60 eluters. For the region of (c , Φ)-space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (c , Φ)-space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations.
Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.
已提出在放射治疗的同时进行原位药物释放，以提高永久性前列腺近距离放射治疗的治疗比。近距离放射治疗源和近距离放射治疗间隔物都被提议作为释放化合物（如纳米颗粒或化疗药物）的潜在洗脱剂。尚未比较这些方法的相对有效性。这项工作对可植入洗脱剂与近距离放射治疗相结合的物理剂量增强进行建模，以确定哪种给药机制提供了提高治疗比的最大机会。
以允许比较不同类型可植入洗脱剂在一系列参数上的相对有效性的方式，对植入的洗脱剂和放射源的联合效应进行建模。从用于I期永久性前列腺植入的治疗计划中提取前列腺几何形状、源和间隔物位置。使用扩散方程的稳态解计算化合物浓度，该方程包括以扩散消除模量（ϕ）为特征的消除项。剂量增强被假定取决于化合物浓度，直至达到饱和浓度（c）。等效均匀剂量（EUD）被用作目标，以确定一系列扩散消除模量、浓度和洗脱剂数量下洗脱剂的最佳配置。统计在上述参数空间中的点处产生最大增强剂量的化合物递送载体，以确定在哪些情况下一种方法比另一种方法更可取的条件。
计算了前列腺体积从14到45 cm、ϕ从0.01到4 mm、c从洗脱剂表面释放的稳态化合物浓度的0.05到7.5倍时植入洗脱剂的增强效果。模拟使用的洗脱剂数量（n）从10到60个洗脱剂。对于导致大部分腺体最大程度敏感的（c，Φ）空间区域，化合物洗脱间隔物或源在EUD上产生相同的增加。在其余大部分（c，Φ）空间中，即使源通常产生更大的最大物理剂量增强，洗脱间隔物导致的EUD也比源更大。将洗脱植入物放置在前列腺的计划位置会比仅使用源或间隔物位置产生更大的增强效果。
洗脱近距离放射治疗间隔物为在常规近距离放射治疗过程中增加EUD提供了机会。纳入额外的针放置允许独立于源放置进行化合物洗脱间隔物放置，从而进一步提高治疗比。需要进一步的工作来了解洗脱剂周围化合物的体内空间分布，并纳入化合物释放和辐射剂量的时间依赖性。
